An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis

• Published in: Molecular cell 2020-01, Vol.77 (2), p.228-240.e7
• Main Authors: Odle, Richard I., Walker, Simon A., Oxley, David, Kidger, Andrew M., Balmanno, Kathryn, Gilley, Rebecca, Okkenhaug, Hanneke, Florey, Oliver, Ktistakis, Nicholas T., Cook, Simon J.
• Format: Article
• Language: English
• Subjects: A549 Cells; Animalia; ATG13; ATG14; autophagy; Autophagy - physiology; CDC2 Protein Kinase - metabolism; CDK1; Cell Line; Cell Line, Tumor; Female; genome; HCT116 Cells; HEK293 Cells; HeLa Cells; HT29 Cells; Humans; lysosomes; Lysosomes - metabolism; macroautophagy; Male; Mechanistic Target of Rapamycin Complex 1 - metabolism; mitosis; Mitosis - physiology; mTOR; nuclear membrane; phosphorylation; Phosphorylation - physiology; RAPTOR; Signal Transduction - physiology; TFEB; ULK1
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2019.10.016

Since nuclear envelope breakdown occurs during mitosis in metazoan cells, it has been proposed that macroautophagy must be inhibited to maintain genome integrity. However, repression of macroautophagy during mitosis remains controversial and mechanistic detail limited to the suggestion that CDK1 phosphorylates VPS34. Here, we show that initiation of macroautophagy, measured by the translocation of the ULK complex to autophagic puncta, is repressed during mitosis, even when mTORC1 is inhibited. Indeed, mTORC1 is inactive during mitosis, reflecting its failure to localize to lysosomes due to CDK1-dependent RAPTOR phosphorylation. While mTORC1 normally represses autophagy via phosphorylation of ULK1, ATG13, ATG14, and TFEB, we show that the mitotic phosphorylation of these autophagy regulators, including at known repressive sites, is dependent on CDK1 but independent of mTOR. Thus, CDK1 substitutes for inhibited mTORC1 as the master regulator of macroautophagy during mitosis, uncoupling autophagy regulation from nutrient status to ensure repression of macroautophagy during mitosis. [Display omitted] •Autophagy initiation is repressed during mitosis, even during nutrient deprivation•RAPTOR phosphorylation in mitosis prevents mTORC1 localization to lysosomes•mTORC1 is inhibited during mitosis•CDK1 phosphorylates autophagy regulators at mTORC1 sites to repress autophagy Odle and colleagues show that while autophagy is usually repressed by the nutrient-responsive mTORC1 kinase complex, this is not the case during mitosis. Instead, CCNB1-CDK1 catalyzes phosphorylation at the same repressive sites, taking over the role of repressing autophagy regulators. Thus, repression of autophagy is ensured regardless of nutrient availability.